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Paper Chase

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells.

Proc. Natl. Acad. Sci. U.S.A.. Jun 24, 2014;111(25):E2622-9.
Kaplinsky J, Li A, Sun A, Coffre M, Koralov SB, Arnaout R.

Department of Pathology andDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115; andDivision of Clinical Informatics, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215;


Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non-antigen-binding antibody region: the heavy-chain variable (VH)-encoded "elbow" between variable and constant domains. By sequencing 2.8 million recombined heavy-chain genes from immature and mature B-cell subsets in mice, we demonstrate a striking gradient in VH gene use as pre-B cells mature into follicular and then into marginal zone B cells. Cells whose antibodies use VH genes that encode a more flexible elbow are more likely to mature. This effect is distinct from, and exceeds in magnitude, previously described maturation-associated changes in heavy-chain complementarity determining region 3, a key antigen-binding region, which arise from junctional diversity rather than differential VH gene use. Thus, deep sequencing reveals a previously unidentified mode of B-cell selection.